Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis

Abstract

Ebolavirus (EBOV) is a member of the filovirus family and causes severe hemorrhagic fever, resulting in death in up to 90% of infected humans. EBOV infection induces massive bystander lymphocyte apoptosis; however, neither the cellular apoptotic pathway(s) nor the systemic implications of lymphocyte apoptosis in EBOV infection are known. In this study, we show data suggesting that EBOV-induced lymphocyte apoptosis in vivo occurs via both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways, as both Fas-associated death domain dominant negative transgenic mice and mice overexpressing bcl-2 were resistant to EBOV-induced lymphocyte apoptosis. Surprisingly, inhibiting lymphocyte apoptosis during EBOV infection did not result in improved animal survival. Furthermore, we show for the first time that hepatocyte apoptosis likely occurs in EBOV infection, and that mice lacking the proapoptotic genes Bim and Bid had reduced hepatocyte apoptosis and liver enzyme levels postinfection. Collectively, these data suggest that EBOV induces multiple proapoptotic stimuli and that blocking lymphocyte apoptosis is not sufficient to improve survival in EBOV infection. These data suggest that hepatocyte apoptosis may play a role in the pathogenesis of EBOV infection, whereas lymphocyte apoptosis appears to be nonessential for EBOV disease progression.

Ebola Virus Does Not Block Apoptotic Signaling Pathways

“…This suggests a potential role for apoptosis in EBOV pathogenesis, at least in rodents. However, it is not clear if the observed apoptotic cells were actually infected with EBOV (7).…”

“…Massive apoptosis of bystander lymphocytes has been observed in fatal cases of EBOV infection, suggesting a role for apoptosis in EBOV pathogenesis (3,5,12). However, blocking of lymphocyte apoptosis in an EBOV mouse model did not increase survival (7). Increased expression of apoptosis-inducing ligands such as TRAIL and Fas has been observed during EBOV infection and could play a role in lymphocyte apoptosis (3, 8-11, 14, 15).…”

“…EBOV productively infects a variety of cells and tissues, with monocytes, macrophages, and dendritic cells representing the early target cells of infection (2). Lymphocytes remain uninfected by EBOV, but a decrease in lymphocyte numbers due to bystander apoptosis is observed during EBOV infection (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Increased expression levels of inducers of apoptosis, including the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL), have been observed during EBOV infection and might play a role in the observed bystander lymphocyte apoptosis (3,9,10,(13)(14)(15).…”

“…Increased expression levels of inducers of apoptosis, including the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL), have been observed during EBOV infection and might play a role in the observed bystander lymphocyte apoptosis (3,9,10,(13)(14)(15). Only limited and contradictory data are available about apoptosis of EBOV-infected cells (7,8,10,16). Moreover, since molecular biology data on the induction and regulation of cell death in EBOV infection are lacking, it is not known if EBOV is able to control cell death signaling pathways in infected cells.…”

Pathogenesis of Ebola Viral Haemorrhagic Fever: TTP-like Syndrome Associated with Hepatic Coagulopathy based on "Two Activation Theory of the Endothelium"

“…Another word, "What is the correct diagnosis for "DIC" that is associated with abnormal coagulation profile?" In Ebola, acute fulminating hepatitis/acute hepatic necrosis, especially multifocal necrosis type, occurs without a good explanation [5,[36][37][38][39][40]. With the "two-activation theory" this can be easily explained by endotheliopathyassociated DIT/VMTD causing hepatic microthrombosis and acute hepatic necrosis syndrome, leading to hepatic coagulopathy [5].…”